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Mac Farlane pitched a seven-minute pilot to Fox in 1998, and the show was greenlit and began production.The show revolves around the adventures of the Griffin family, consisting of father Peter Griffin, a bumbling yet well-intentioned blue-collar worker; Lois, a pretty, stay-at-home mother and piano teacher who is a member of the wealthy Pewterschmidt family; Meg, their often-bullied teenage daughter who is also constantly ridiculed or ignored by the family; Chris, their awkward teenage son, who is overweight, unintelligent and, in many respects, is simply a younger version of his father; and Stewie, their diabolical infant son of ambiguous sexual orientation who has adult mannerisms and uses stereotypical archvillain phrases.Living with the family is their witty, smoking, martini-swilling, sarcastic, English-speaking anthropomorphic dog Brian, though he is still considered a pet in many ways.A spin-off series, The Cleveland Show, featuring Cleveland Brown, aired from September 27, 2009, to May 19, 2013."The Simpsons Guy", a crossover episode with The Simpsons, aired on September 28, 2014.

Many tie-in media have been released, including Stewie Griffin: The Untold Story, a straight-to-DVD special released in 2005; Family Guy: Live in Vegas, a soundtrack-DVD combo released in 2005, featuring music from the show as well as original music created by Mac Farlane and Walter Murphy; a video game and pinball machine, released in 20, respectively; since 2005, six books published by Harper Adult based on the Family Guy universe; and Laugh It Up, Fuzzball: The Family Guy Trilogy (2010), a series of parodies of the original Star Wars trilogy.

In 2008, Mac Farlane confirmed that the cast was interested in producing a feature film and that he was working on a story for a film adaptation.

Mac Farlane resided in Providence during his time as a student at Rhode Island School of Design, and the show contains distinct Rhode Island landmarks similar to real-world locations.

Mac Farlane often borrows the names of Rhode Island locations and icons such as Pawtucket and Buddy Cianci for use in the show.

Recurring characters appear alongside the Griffin family.

These include the family's neighbors: sex-crazed airline pilot bachelor Quagmire; African-American deli owner Cleveland and his wife Loretta (later Donna); paraplegic police officer Joe, his wife Bonnie, their son Kevin and their baby daughter Susie; neurotic Jewish pharmacist Mort, his wife Muriel, and their geeky and annoying son Neil; and elderly child molester Herbert.